Jiangsu Provincial Key Lab for the Chemistry and Utilization of Agro-forest Biomass, Jiangsu Key Lab of Biomass-based Green Fuels and Chemicals, Co-Inovation Center for Efficient Processing and Utilization of Forest Products, College of Chemical Engineering, Nanjing Forestry University, Nanjing 210037, PR China.
Jiangsu Provincial Key Lab for the Chemistry and Utilization of Agro-forest Biomass, Jiangsu Key Lab of Biomass-based Green Fuels and Chemicals, Co-Inovation Center for Efficient Processing and Utilization of Forest Products, College of Chemical Engineering, Nanjing Forestry University, Nanjing 210037, PR China.
Bioorg Chem. 2020 Jul;100:103845. doi: 10.1016/j.bioorg.2020.103845. Epub 2020 Apr 10.
Phosphatidylinositol 3-kinase (PI3K) is one of the most attractive therapeutic targets for cancer treatment. In this study, a series of new 2-arylthio- and 2-arylamino-1H-benzo[d]imidazole derivatives of dehydroabietic acid were designed, synthesized and characterized by H NMR, C NMR, IR and MS spectra analyses. In the in vitro anticancer assay, some title compounds showed significant inhibitory activities against four cancer cell lines (HCT-116, MCF-7, HeLa and HepG2). Among them, compound 9g exhibited the most potent activity with IC values of 0.18 ± 0.03, 0.43 ± 0.05, 0.71 ± 0.08 and 0.63 ± 0.09 μM against four cancer cell lines, and considerably lower cytotoxicity to human gastric mucosal cell line Ges-1 (IC: 21.95 ± 0.73 μM). Besides, compound 9g displayed a certain selective activity to PI3Kα (IC = 0.012 ± 0.002 μM) over PI3Kβ, γ and δ, and meanwhile, it can remarkably decrease the expression level of p-Akt (Ser473). In addition, compound 9g could increase intracellular reactive oxygen species level, decrease mitochondrial membrane potential, upregulate Bax and cleaved caspase-3/9 levels, downregulate Bcl-2 level and thus induce the apoptosis of HCT-116 cells in a dose-dependent manner. The results suggested that compound 9g could be considered as a promising PI3Kα inhibitor.
磷酸肌醇 3-激酶（PI3K）是癌症治疗中最有吸引力的治疗靶点之一。在这项研究中，设计、合成并通过 H NMR、C NMR、IR 和 MS 谱分析对一系列新的去氢枞酸 2-芳基硫代-和 2-芳基氨基-1H-苯并[d]咪唑衍生物进行了表征。在体外抗癌测定中，一些标题化合物对四种癌细胞系（HCT-116、MCF-7、HeLa 和 HepG2）表现出显著的抑制活性。其中，化合物 9g 表现出最强的活性，对四种癌细胞系的 IC 值分别为 0.18±0.03、0.43±0.05、0.71±0.08 和 0.63±0.09μM，对人胃黏膜细胞系 Ges-1 的细胞毒性也明显较低（IC：21.95±0.73μM）。此外，化合物 9g 对 PI3Kα（IC=0.012±0.002μM）表现出一定的选择性，而对 PI3Kβ、γ和δ的选择性较低，同时，它可以显著降低 p-Akt（Ser473）的表达水平。此外，化合物 9g 可以增加细胞内活性氧水平，降低线粒体膜电位，上调 Bax 和 cleaved caspase-3/9 水平，下调 Bcl-2 水平，从而以剂量依赖的方式诱导 HCT-116 细胞凋亡。结果表明，化合物 9g 可被认为是一种有前途的 PI3Kα 抑制剂。
